Antimicrobial peptides (AMPs) represent a first line of defense against microbes for many species. AMPs are typically small (12-80 amino acids) cationic amphiphiles. There are two types of AMPs comprising ribosomally and nonribosomally synthesized peptides. Over 700 AMPs have been identified and are generally α-helical (magainin and cecropin) or disulfide-rich β-sheets (bactenecin and defensin). Although the peptides are composed of many different sequences, their physiochemical properties are remarkably similar. They adopt an amphiphilic architecture with positively charged groups segregated to one side of the secondary structure and hydrophobic groups on the opposite surface. In mammals, the peptides are produced and secreted in skin, mucosal surfaces and neutrophils, and act locally in response to infection. It is the overall physiochemical properties that are largely responsible for biological activity of these peptides.
Some antimicrobial activities of host defense proteins have been linked to direct cytotoxic actions and modulation of the innate immune system. Their direct antimicrobial activities are proposed to involve both membrane and non-membrane effects. Antimicrobial peptides have remained an effective weapon against bacterial infection over evolutionary time indicating that their mechanism of action thwarts bacterial responses which lead to resistance against toxic substances. This premise is supported by direct experimental data showing that no appreciable resistance to the action of the antimicrobial peptides occurs after multiple serial passages of bacteria in the presence of sub-lethal concentrations of the peptides.
There is a dire need for development of new antimicrobial agents that attack new targets to evade resistance issues that limit the usefulness of many antibiotics. Furthermore, these new agents should exert their antimicrobial activity via mechanisms that bacteria do not effectively resist. A series of non-peptidic analogues have been developed that have many advantages over peptides because of their small size, which increases stability and enhances tissue distribution, and ability to fine-tune their physical properties for optimization of potency and safety. A series of arylamide compounds that mimic structural properties of the antimicrobial peptides were found to have potent antibacterial activities and wide selectivity ratios versus mammalian cells.